Osteoarthritis (OA) is a disease affecting joints following (a) cartilage injury; (b) exposure to excessive load-bearing, or repetitive use; or (c) general aging. OA affects 10% of the world's 60 years and older population. It is characterized by joint pain and dysfunction, degradation of joint cartilages, decreased proteoglycan content in articular cartilage, production of osteophytes (calcified tissue in the margins of the articular cartilage) and fibrosis of the synovial lining of the joint. The unchecked actions of MMPs and elevated activation of transforming growth factor beta (TGFβ) have been implicated as a primary cause for osteoarthritic cartilage degradation.
TGFβ biological activity is modulated by protease-mediated activation to disassemble latency complexes. TGFβ is secreted as a small latent complex that is covalently associated with latent TGFβ binding protein 1 (LTBP1) to form the TGFβ large latent complex. LTBP1 anchors the TGFβ large latent complex (TGFβ LLC) to the extracellular matrix (ECM). This complex must be released from the extracellular matrix in order for TGFβ to become activated for signaling. TGFβ is secreted as a small latent complex in non-covalent association with its N-terminal latency associated peptide, β-LAP. β-LAP and LTBP1 have been implicated in proper processing, secretion, and guidance of the TGFβ LLC to the ECM for storage. Analysis of TGFβ distribution in bone indicates that the bulk of TGFβ is stored in the ECM as a 100 kD TGFJ3 small latent complex (TGFJ3 SLC) and a 270 kD TGFβ LLC. TGFβ is only capable of binding the signaling receptor complex in its mature, 25 kD, homodimeric form. Therefore, activation must occur through a tightly controlled series of proteolytic steps. Plasmin, elastase, chymase, thrombospondin, MMP9, MMP3 and MMP13 have all been implicated in activation of TGFβ resulting in release of the mature receptor-binding homodimer. In addition, an alternatively spliced short form of LTBP1 can form the large latent complex with TGFβ. It has been demonstrated that this form of the TGFβ LLC including the short LTBP1 can be more readily removed from the extracellular matrix.
MMP inhibitors, such as batimastat, marimastat, CGS-27023A, and prinomastat, have been used to treat OA. However, those attempts have resulted in severe side-effects known as MMP-induced musculoskeletal syndrome which includes joint stiffness, inflammation, and symptoms manifested as pain in the hands, arms, and shoulders. Therefore, there remains a need for compounds and methods for inhibiting activation of TGFβ, and treating OA as well as other TGFβ-associated indications without the adverse effect of MMP-induced musculoskeletal syndrome.